Drug and Toxin Induced Liver Injury

Slide 1 · Drug- and Toxin-Induced

Liver Injury

Pathogenesis • morphologic patterns • clinicopathologic diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Distinguish dose-dependent toxicity from idiosyncratic reactions.

Link reactive metabolites, hepatic zonation, and hepatocellular necrosis.

Recognize the principal histologic patterns of injury.

Integrate exposure chronology, laboratory phenotype, and exclusion of competing causes.

Slide 3 · DILI is a clinicopathologic diagnosis

Drug-induced liver injury (DILI) encompasses hepatic injury due to medications and other xenobiotics.

The same exposure may create more than one histologic or biochemical pattern.

Neither the presenting symptoms nor the biopsy appearance is individually pathognomonic.

Diagnosis requires exposure chronology and exclusion of alternatives.

Slide 4 · Why the liver is especially vulnerable

Portal inflow delivers absorbed xenobiotics to hepatocytes.

Hepatic biotransformation may detoxify compounds or generate toxic intermediates.

Compartment-specific enzyme activity helps determine the distribution of injury.

Xenobiotic exposure

Hepatic metabolism

Reactive intermediates

Parenchymal injury

Slide 5 · The clinical burden extends beyond acute hepatitis

DILI as a major cause of acute liver failure in the United States.

Among patients in the cited US DILIN cohort, 10% died or required transplantation.

In that cohort, 17% developed chronic liver disease.

10%

Death or transplantation

17%

Chronic liver disease

Cohort outcomes reported; Not the risk for every exposed patient.

Slide 6 · Potential hepatotoxins extend beyond prescriptions

Prescription and nonprescription medicines.

Herbal products and nutritional supplements.

Poisonous plants and fungi, including Amanita mushrooms.

Household or industrial chemicals, including solvents and pesticides.

Medicines

Supplements

Plants & fungi

Chemicals

Slide 7 · The exposure-to-injury interval varies

Toxic injury may become apparent soon after exposure.

Other reactions emerge after weeks or months.

A convincing assessment must reconstruct the onset, duration, and cessation of all suspected exposures.

Exposure

Latency

Liver injury

Withdrawal / follow-up

Slide 8 · Two broad mechanisms organize DILI

Intrinsic toxicity

Idiosyncratic injury

Dose-dependent

Often acute

Acetaminophen is classic

Unpredictable

Often delayed

May involve immune or host factors

Slide 9 · Intrinsic injury: Dose predicts risk

In direct toxicity, the exposure or its toxic metabolite injures hepatocytes.

Acetaminophen is the classical example.

Other direct hepatotoxins cited include organic solvents and mushroom toxins.

Higher effective exposure

Metabolite / toxin burden

Cell injury

Hepatic necrosis

Slide 10 · Idiosyncratic injury: Host susceptibility matters

Most drug-induced injury described in this section is idiosyncratic.

Only a minority of exposed individuals develop the reaction.

A typical latency of one to three months is described, although individual presentations vary.

A therapeutic dose does not exclude a serious idiosyncratic reaction.

Slide 11 · Contrasting the intrinsic and idiosyncratic patterns

Feature

Intrinsic

Idiosyncratic

Predictability

Relatively predictable

Unpredictable

Dose relationship

Characteristic

Not simply dose-dependent

Example

Acetaminophen

Many antimicrobials

Histology

Often necrosis dominant

Often hepatitis-like

Slide 12 · Reactive metabolites can initiate tissue injury

Hepatocytes enzymatically convert many parent compounds to intermediates.

Some intermediates are more reactive than the parent drug.

Downstream effects may include cell damage, inflammation, or necrosis.

Parent drug

Oxidative metabolism

Reactive intermediate

Tissue response

Slide 13 · Cytochrome P450 links metabolism to zonal injury

Cytochrome P450 enzymes mediate many xenobiotic reactions.

Higher metabolic activity in the centrilobular region.

Perivenular (zone 3) necrosis is therefore a recurring morphologic clue.

CV

PT

PT

PT

PT

Zone 3

PT: Portal tract • CV: Central vein

Simplified hepatic lobule: Periportal to perivenular gradient.

Slide 14 · Zone 3 necrosis reflects metabolic geography

Centrilobular and perivenular identify the region nearest a terminal hepatic venule.

Metabolic activation of some xenobiotics is particularly important in this zone.

Zonal necrosis supports a mechanism but does not uniquely establish DILI.

CV

PT

PT

PT

PT

Zone 3

PT: Portal tract • CV: Central vein

Schematic topography; Not a histologic photomicrograph.

Slide 15 · Enzyme induction may amplify co-exposure toxicity

Rifampicin, phenytoin, isoniazid, tobacco smoke, and ethanol as enzyme-inducing exposures.

Induction can alter formation of reactive metabolites from another compound.

Clinical interpretation must consider combinations rather than one drug in isolation.

Enzyme induction

Altered biotransformation

Toxic metabolite formation

Greater susceptibility

Slide 16 · Genetic metabolism affects susceptibility

NAT2 variation as one contributor to isoniazid hepatotoxicity.

Reduced N-acetyltransferase activity can increase hepatic exposure to relevant compounds.

A genetic predisposition does not imply inevitable injury in every carrier.

NAT2 variation

Reduced enzymatic activity

Higher drug exposure

Injury susceptibility

Slide 17 · Immune mechanisms contribute to some reactions

Some idiosyncratic reactions are thought to involve hypersensitivity to drugs or their metabolites.

An inflammatory pattern may include lymphocytes, eosinophils, and plasma cells.

These features suggest a reaction pattern but are not specific for an individual drug.

An inflammatory infiltrate is not proof of drug causality.

Slide 18 · Antimicrobials are prominent idiosyncratic culprits

The textbook attributes nearly half of idiosyncratic cases to antimicrobial agents.

Examples across its pattern table include antibiotics and isoniazid.

Associated lesions range from hepatitis to cholestatic injury or granulomas.

Acute hepatitis

Cholestatic hepatitis

Granulomas

Chronic hepatitis

Slide 19 · Many therapeutic classes may injure the liver

The implicated classes include cardiovascular drugs, CNS drugs, antineoplastic agents, and NSAIDs.

Immune-checkpoint inhibitors such as PD-1/PD-L1/CTLA-4 agents are also included.

Drug class alone cannot predict the histologic pattern in an individual patient.

Cardiovascular

CNS agents

Oncology

Analgesics / NSAIDs

Slide 20 · Supplements and environmental exposures require explicit inquiry

Herbal and nutritional products are implicated in idiosyncratic injury.

Patients may not spontaneously report nonprescription or traditional preparations.

Fungal toxins, solvents, and industrial exposures broaden the differential.

Record every ingested, inhaled, and occupational exposure.

Slide 21 · Acetaminophen provides the model of intrinsic injury

At therapeutic exposure, the major fraction is detoxified by phase II metabolism.

A small fraction undergoes cytochrome-dependent formation of NAPQI.

Normally, glutathione conjugates and inactivates NAPQI.

Acetaminophen

Phase II

Conjugation

CYP-mediated

NAPQI formation

Urinary excretion

GSH required for NAPQI detoxification

Original editable metabolic pathway schematic.

Slide 22 · Glucuronidation and sulfation are protective

Glucuronide and sulfate conjugation as the major metabolic pathway.

These water-soluble conjugates permit urinary elimination.

A smaller oxidative pathway generates NAPQI and requires glutathione detoxification.

Acetaminophen

Phase II

Conjugation

CYP-mediated

NAPQI formation

Urinary excretion

GSH inactivates NAPQI

Original editable metabolic pathway schematic.

Slide 23 · Overdose shifts the NAPQI balance

With excessive acetaminophen, the burden of reactive NAPQI increases.

Glutathione stores are depleted or insufficient to detoxify the accumulated metabolite.

Unconjugated NAPQI promotes hepatocyte injury.

Excess acetaminophen

Increased NAPQI burden

Inadequate GSH defense

Hepatocellular damage

Slide 24 · Protein adducts and oxidative stress mediate toxicity

NAPQI binds covalently to hepatic proteins.

Mitochondrial dysfunction contributes to cellular damage.

Depletion of glutathione increases susceptibility to reactive oxygen species.

NAPQI–protein adducts

Mitochondrial damage

GSH depletion

Oxidative injury

Slide 25 · Acetaminophen injury preferentially affects zone 3

Centrilobular hepatocytes are vulnerable to metabolic activation of acetaminophen.

The source describes confluent perivenular necrosis, sometimes extending across lobules.

Inflammation may be relatively limited compared with extensive necrosis.

CV

PT

PT

PT

PT

Zone 3

PT: Portal tract • CV: Central vein

Schematic distribution of necrosis, not a tissue section.

Slide 26 · Necrosis-dominant injury differs from hepatitis-dominant injury

Necrosis dominant

Inflammation dominant

Confluent cell loss

Sparse infiltrate

Acetaminophen; Halothane

Lymphocytes ± other cells

Variable single-cell necrosis

Many antimicrobials

Slide 27 · Acetaminophen poisoning evolves clinically

Early complaints may include nausea, vomiting, or diarrhea.

A subsequent interval can be followed by jaundice and biochemical evidence of hepatic injury.

Severe intoxication can progress to acute liver failure.

Ingestion

Early GI symptoms

Hepatic injury

Possible liver failure

Slide 28 · N-acetylcysteine targets the detoxification deficit

N-acetylcysteine as a therapy that restores glutathione.

Early administration is particularly beneficial.

Clinical management must not be delayed by an apparently mild initial presentation.

N-acetylcysteine

Restoration of GSH

NAPQI detoxification

Reduced injury risk

Slide 29 · Severe intrinsic toxicity can involve other organs

Acetaminophen poisoning may lead to acute liver failure.

The textbook also notes concurrent renal injury in some patients.

Widespread hepatocellular necrosis can require transplantation.

A hepatotoxin may produce systemic or multiorgan consequences.

Slide 30 · Direct-acting toxins are not limited to acetaminophen

Organic solvents can cause severe liver injury.

Certain poisonous mushrooms contain potent hepatic toxins.

Exposure reconstruction must include environmental and dietary sources.

Acetaminophen

Organic solvents

Toxic mushrooms

Other xenobiotics

Slide 31 · The biopsy vocabulary spans multiple patterns

Patterns described include hepatitic, cholestatic, steatotic, vascular, granulomatous, fibrosing, and neoplastic alterations.

The histologic reaction may combine several patterns in one biopsy.

Morphology characterizes the injury but cannot independently identify its cause.

Hepatitic

Cholestatic

Steatotic

Vascular / other

Slide 32 · Three major clinical-biochemical patterns

Hepatocellular

Cholestatic / mixed

ALT-predominant

Hepatitis-like injury

Necrosis may be present

ALP-predominant or dual

Bile accumulation / duct injury

Ductular reaction may occur

Slide 33 · Acute hepatitis: Inflammation dominates

Lobular lymphocytic inflammation is conspicuous.

Plasma cells and eosinophils may be present in variable proportions.

Single-cell necrosis or confluent necrosis may accompany the infiltrate.

Schematic inflammatory pattern; Not an H&E section.

Slide 34 · Acute hepatitis: Necrosis dominates

Confluent hepatocyte necrosis is the major abnormality.

Inflammation may be relatively sparse.

The textbook associates this pattern with acetaminophen and halothane.

Schematic hepatocyte loss; Not an H&E section.

Slide 35 · DILI can resemble viral or autoimmune hepatitis

Potentially shared features

Needed to attribute DILI

Interface / lobular activity

Plasma cells or eosinophils

Hepatocyte necrosis

Credible exposure chronology

Competing-cause work-up

Trajectory after withdrawal

Slide 36 · Centrizonal accentuation is useful but nonspecific

In the hepatitic pattern, injury may cluster near terminal hepatic venules.

The source identifies centrizonal necrosis as a common feature.

It cannot distinguish every medication reaction from other causes of zonal injury.

CV

PT

PT

PT

PT

Zone 3

PT: Portal tract • CV: Central vein

Schematic zonation.

Slide 37 · Bland hepatocellular cholestasis

Bile accumulates without a strong accompanying inflammatory infiltrate.

Contraceptive and anabolic steroids, some antibiotics, and antiretroviral therapy as associations.

The absence of florid hepatitis is central to the “bland” descriptor.

Schematic bile retention; Not a microscopic specimen.

Slide 38 · Cholestatic hepatitis combines two injury processes

Cholestasis occurs together with lobular necroinflammatory activity.

In some cases the bile ducts are damaged or destroyed.

Textbook examples include antibiotics, phenothiazines, and statins.

Drug reaction

Bile retention

Lobular inflammation

Possible duct injury

Slide 39 · Persistent cholestasis may reflect duct loss

Some bile duct–centered reactions progress to chronic cholestasis.

Ductular reaction may coexist with duct injury.

A minority develop bile duct loss, making persistence possible after exposure ceases.

Schematic portal bile duct alteration.

Slide 40 · Chronic hepatitis is a recognized drug pattern

Acute injury

Chronic injury

Lobular activity

Necrosis ± cholestasis

Variable inflammation

Portal-based inflammation

Progressive fibrosis possible

May resemble chronic hepatitis

Slide 41 · Some drugs produce a steatotic phenotype

Large and small lipid droplets can appear within hepatocytes.

Corticosteroids, methotrexate, and parenteral nutrition among associations.

Drug-associated fatty change requires differentiation from other steatotic liver diseases.

Schematic hepatocellular fat accumulation.

Slide 42 · Macrovesicular and microvesicular fat differ

Macrovesicular

Microvesicular

Dominant large fat vacuole

Nucleus often displaced

Several metabolic and drug causes

Numerous small vacuoles

Mitochondrial dysfunction implicated

Valproate; Tetracycline; Others

Slide 43 · Microvesicular steatosis implicates mitochondria

The textbook links this phenotype with mitochondrial dysfunction.

Examples include tetracycline, valproic acid, and zidovudine.

Diffuse mitochondrial failure can impair liver function even without massive necrosis.

Mitochondrial injury

Defective lipid handling

Fine fat droplets

Hepatic dysfunction

Slide 44 · Drug-related steatohepatitis is a separate phenotype

Amiodarone, tamoxifen, irinotecan, and methotrexate may produce steatohepatitis-like injury.

The table mentions steatohepatitis with Mallory hyaline for selected agents.

Histologic overlap with metabolic and alcohol-associated steatohepatitis requires clinical context.

Conceptual combination of fat and inflammatory injury.

Slide 45 · Long-term injury can culminate in fibrosis

Periportal and pericellular fibrosis may develop in toxic or drug-associated injury.

The source lists methotrexate, alcohol, enalapril, and retinoids among associations.

Cirrhosis is possible, but not the typical outcome of every DILI episode.

Sustained injury

Fibrogenic response

Progressive fibrosis

Possible cirrhosis

Slide 46 · Granulomatous reactions broaden the differential

Noncaseating epithelioid granulomas may accompany drug reactions.

Examples in the source include sulfonamides, amiodarone, and isoniazid.

Allopurinol is associated with fibrin-ring granulomas in the source table.

Schematic granulomatous reaction.

Slide 47 · Vascular injury may be the dominant lesion

Toxins or drugs can damage sinusoidal or venous endothelium.

The resulting pathology may involve obstruction, congestion, or blood-filled spaces.

These changes are distinct from hepatocyte-centered hepatitis.

Sinusoidal obstruction

Budd–Chiari pattern

Peliosis hepatis

Vascular congestion

Slide 48 · Sinusoidal obstruction syndrome

SINUSOID

Congested sinusoid

Obstructed central venular outflow

Original conceptual vascular schematic; Not clinical histology.

Slide 49 · Peliosis hepatis features blood-filled cavities

Blood-filled cavities within parenchyma

Original conceptual vascular schematic; Not clinical histology.

Slide 50 · Budd–Chiari is an outflow-obstruction phenotype

Hepatic venous outflow obstruction is a distinct vascular disorder.

The table lists oral contraceptives as a relevant association.

This association should not be mistaken for proof of causality in an individual patient.

Predisposing exposure

Hepatic venous thrombosis

Outflow obstruction

Hepatic congestion

Slide 51 · Some exposures are linked to hepatic neoplasia

Neoplastic lesion

Associated agent

Hepatocellular adenoma

Oral contraceptives; Anabolic steroids

Hepatocellular carcinoma

Alcohol; Thorotrast

Cholangiocarcinoma

Thorotrast

Angiosarcoma

Thorotrast; Vinyl chloride

Slide 52 · Patterns and representative associations

Pattern

Morphologic emphasis

Examples

Bland cholestasis

Bile without much inflammation

Anabolic steroids

Hepatitic

Inflammatory injury ± necrosis

Antimicrobials

Necrosis dominant

Confluent necrosis

Acetaminophen

Microvesicular fat

Numerous small fat droplets

Valproate; Tetracycline

Slide 53 · Additional lesions and associated agents

Pattern

Diagnostic structure

Examples

Granulomatous

Epithelioid or fibrin-ring granulomas

Isoniazid; Allopurinol

Sinusoidal obstruction

Sinusoidal / venular injury

Oxaliplatin; Azathioprine

Peliosis

Blood-filled cavities

Anabolic steroids; Tamoxifen

Steatohepatitis

Fat with hepatocyte injury

Amiodarone; Irinotecan

Slide 54 · Presentation ranges from silent injury to liver failure

DILI may first be recognized as abnormal liver enzyme tests.

Some patients develop jaundice or an acute hepatitis-like illness.

Severe cases progress to failure; Others manifest prolonged cholestasis or chronic disease.

Biochemical injury

Symptomatic hepatitis

Severe dysfunction

Recovery or chronicity

Slide 55 · Biochemistry suggests pattern, not etiology

Laboratory pattern

Interpretive limitation

ALT predominance

ALP predominance

Both increased

Pattern is not cause

Histology may overlap

Timing matters

Slide 56 · A medication history should be chronological

Document the date every potentially relevant agent was started.

Record dose changes, combinations, interruptions, and withdrawal.

Link the first laboratory or symptomatic abnormality to this exposure map.

Drug started

Dose / exposure changes

First abnormality

Stopped / evolved

Slide 57 · Establish an alternative-cause differential

Viral hepatitis and autoimmune hepatitis can produce similar inflammation.

Steatotic liver disease can explain fatty change or steatohepatitis.

Biliary and vascular disease may mimic cholestatic or venous patterns.

Viral infection

Autoimmune hepatitis

Steatotic disease

Biliary / vascular causes

Slide 58 · Biopsy is a pattern-recognition tool

Hepatic tissue can show necrosis, portal/lobular activity, duct injury, fat, granulomas, or vascular injury.

More than one pattern may coexist.

The pathology report should express degree and distribution of injury without assuming causality.

Pathology supports an attribution; It rarely proves the responsible drug.

Slide 59 · Improvement after withdrawal supports attribution

A temporal relationship between exposure and onset is necessary for diagnosis.

Excluding plausible alternative causes strengthens the assessment.

Recovery after stopping the agent supports DILI in many cases, but not every injury resolves promptly.

Exposure history

Compatible phenotype

Alternative causes assessed

Course after withdrawal

Slide 60 · An adverse drug reaction may mimic autoimmunity

Overlapping findings

Discriminating context

Plasma-cell inflammation

Interface injury

Autoantibodies may occur

Medication chronology

Other autoimmune evidence

Clinical course

Slide 61 · Teaching case: Marked necrosis after overdose

Illustrative scenario: An adult presents after an excessive acetaminophen ingestion.

The biopsy concept is zone 3 confluent necrosis with limited inflammation.

Which mechanism most directly explains the zonal damage?

Discuss the morphologic mechanism and differential

Slide 62 · Case interpretation: Intrinsic hepatotoxicity

An exposure–response relationship is central to this case.

Glutathione normally detoxifies NAPQI; Overdose overwhelms this defense.

Centrilobular necrosis is compatible with metabolic activation of the toxin.

NAPQI formation

Glutathione deficit

Zone 3 injury

Confluent necrosis

Slide 63 · Teaching case: Antibiotic-associated hepatitis

Illustrative scenario: Liver tests become abnormal weeks after a new antimicrobial.

Liver biopsy shows lymphocytic lobular hepatitis with eosinophils and scattered cell death.

Why is histology alone insufficient to confirm a drug reaction?

Discuss the morphologic mechanism and differential

Slide 64 · Case interpretation: Idiosyncratic hepatitis

The latency is compatible with an idiosyncratic reaction.

An inflammatory infiltrate does not identify the responsible molecule.

The diagnostic case strengthens when alternatives are excluded and injury improves after withdrawal.

Drug introduced

Delayed onset

Hepatitic phenotype

Dechallenge / exclusion

Slide 65 · Teaching case: Cholestasis with little inflammation

Illustrative scenario: Cholestatic liver tests follow an anabolic steroid exposure.

Schematic biopsy pattern: Accumulated bile with little lobular inflammation.

Which named pattern best captures this morphology?

Discuss the morphologic mechanism and differential

Slide 66 · Case interpretation: Bland cholestasis

The pattern is defined by bile retention with minimal inflammatory activity.

Steroid-associated cholestasis is included among the source examples.

Other cholestatic causes still require clinical exclusion.

Schematic; No actual histopathology supplied.

Slide 67 · A structured final pathology synthesis

State the predominant pattern: Hepatitic, cholestatic, mixed, or another recognizable lesion.

Describe severity, distribution, bile duct abnormalities, fat, vascular injury, and fibrosis as applicable.

Correlate the findings with drug exposure and the broader clinical work-up.

Pattern

Distribution / severity

Potential mimics

Clinical correlation

Slide 68 · High-yield distinctions

Predictable intrinsic injury is exemplified by acetaminophen and necrosis-dominant pathology.

Idiosyncratic injury frequently resembles acute hepatitis and may follow a delayed onset.

Steatotic, cholestatic, vascular, granulomatous, and neoplastic lesions also belong in the spectrum.

Diagnosis rests on chronology, competing-cause exclusion, and follow-up.

Slide 69 · References and suggested reading

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Elsevier; 2026.

Drug- and Toxin-Induced Liver Injury: pathogenesis, morphologic patterns, and clinical features.

Acetaminophen: hepatic metabolism, reactive intermediates, and glutathione-dependent detoxification.